Randomised Evaluation of COVID-19 Therapy: the RECOVERY trial Martin Landray University of Oxford, UK on behalf of the RECOVERY trial investigators www.recoverytrial.net
Background Emerging pandemic caused by a new virus - For most people, self-limiting viral illness - For hospitalised patients, 10-20% mortality - For ventilated patients, 40-50% mortality Daily confirmed new cases USA UK Italy
Background Unprecedented clinical challenge - Overstretched health service (availability of beds, staff, and ventilators) - Huge time pressures and personal stress for frontline medical staff - Large numbers of unwell, anxious, and often elderly patients UK New Cases UK Deaths
Background Unprecedented clinical challenge - Overstretched health service (availability of beds, staff, and ventilators) - Huge time pressures and personal stress for frontline medical staff - Large numbers of unwell, anxious, and often elderly patients Huge therapeutic uncertainty - Many candidates - Many opinions (from many sources) - No reliable data (uncontrolled case series, inconclusive randomized trials)
Background Addressing the therapeutic challenge - Unlikely to be a single “big win” - Moderate benefits plausible Moderate effects are worthwhile - There were ~15,000 deaths from COVID-19 in the US last week - Reducing mortality by one- fifth would “save” ~3,000 lives
Background Differentiating moderate benefits from no benefit (or harm) requires: - RANDOMIZATION - Comparison vs. CONTROL group not receiving the drug - LARGE numbers Mortality 90% power For example: @2P=0.01 20% 30% Proportional risk reduction 20% 5,600 3,300 30% 2,400 1,400
Prioritising treatments to study Initial prioritisation principles: - Potentially effective (based on prior pre-clinical & clinical data) - Major safety issues understood - Sufficient treatment available for large-scale recruitment - Potential to rapidly scale up as a clinical treatment (if shown to be effective) Three broad categories: - Re-purposed drugs widely used in other conditions - Drugs normally restricted to specialist settings (e.g. immunomodulation) - Treatments targeted at SARS-CoV-2 (e.g. convalescent plasma, anti-spike Ab)
Quality by Design Three key principles: - Obtain robust results that can rapidly impact care - Consider well-being of patients - Consider well-being of staff Focus only on what matters - Leave orthodoxy, habits, and traditional practices behind - Communicate and collaborate - Transparency (with research, medical, patient, public, media, etc)
A coordinated approach Coordinated, collaborative approvals - Single regulatory agency (MHRA) - Single Ethics Committee (IRB) covers the whole country - Common contract Prioritisation of resources - Chief Medical Officer: clinical trial enrolment is part of delivering clinical care - National Institute for Health Research Clinical Research Network: mobilised research nurses at every hospital - Department of Health: procured & supplied treatment - NHS Digital: access to linked national health data from multiple sources
Sticking to the principles of Good Clinical Practice “ Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).” (ICH E6(R2) section 2.8).
Sticking to the principles of Good Clinical Practice “ Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).” (ICH E6(R2) section 2.8). At each hospital, a lead investigator will be responsible for trial activities but much of the work will be carried out by medical staff attending patients with COVID-19 within the hospital and by hospital research nurses, medical students and other staff with appropriate education, training, and experience.
Sticking to the principles of Good Clinical Practice “ Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).” (ICH E6(R2) section 2.8). At each hospital, a lead investigator will be responsible for trial activities but much of the work will be carried out by medical staff attending patients with COVID-19 within the hospital and by hospital research nurses, medical students and other staff with appropriate education, training, and experience. The tasks that they are required to perform under this protocol are similar to those that they perform in the other aspects of their roles as NHS staff.
Sticking to the principles of Good Clinical Practice “ Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).” (ICH E6(R2) section 2.8). At each hospital, a lead investigator will be responsible for trial activities but much of the work will be carried out by medical staff attending patients with COVID-19 within the hospital and by hospital research nurses, medical students and other staff with appropriate education, training, and experience. The tasks that they are required to perform under this protocol are similar to those that they perform in the other aspects of their roles as NHS staff. No additional training in GCP is required.
RECOVERY trial design ELIGIBLE PATIENTS 1. Age ≥18 years 2. Admitted to hospital 3. Proven or suspected SARS- CoV-2 infection
Identification and invitation • All adult patients with proven or suspected SARS-CoV-2 infection admitted should be considered for trial • Should be discussed with senior member of clinical team and assuming 1. All eligibility criteria are met; and 2. No medical history that might, in the opinion of the attending clinician, put the patient at significant risk if he/she were to participate in the trial, the patient should be offered participation • If one or more of the treatment arms is not available or believed, by the attending clinician, to be contraindicated (or definitely indicted), then the patient can be randomised between the remaining arms
Informed consent
Informed consent • Simple 2 page information sheet & 1 page form • Option for witnessed consent • if participant cannot read or sign for themselves • If infection control procedures do not allow ICF out of the ‘red zone’ • Option for legal representative • if patient lacks capacity
Informed consent • Simple 2 page information sheet & 1 page form • Option for witnessed consent • if participant cannot read or sign for themselves • If infection control procedures do not allow ICF out of the ‘red zone’ • Option for legal representative • if patient lacks capacity
RECOVERY trial design No additional treatment ELIGIBLE PATIENTS Lopinavir-ritonavir 400/100 mg bd PO for 10 days 1. Age ≥18 years 2. Admitted to R Dexamethasone hospital 6 mg od PO/IV for 10 days 3. Proven or suspected SARS- Hydroxychloroquine CoV-2 infection See protocol for dosing Azithromycin 500 mg od PO/IV for 10 days
Randomisation
Randomisation
Randomisation
Randomisation
Randomisation
RECOVERY trial design No additional treatment OUTCOMES ELIGIBLE PATIENTS Lopinavir-ritonavir 400/100 mg bd PO for 10 days Primary: all-cause 1. Age ≥18 years death Secondary: 2. Admitted to R Dexamethasone • Duration of hospital 6 mg od PO/IV for 10 days hospitalisation • Need for 3. Proven or ventilation suspected SARS- • Need for renal Hydroxychloroquine CoV-2 infection replacement See protocol for dosing therapy Azithromycin 500 mg od PO/IV for 10 days
Follow-up • Simple on-line form completed by research nurses • Which treatments did the patient receive • COVID-19 test result • Discharge status & date • Use of ventilation • Linkage to national data sources • Vital status, death certificate • Coded hospital episode statistics (diagnoses, procedures) • Intensive Care audit data, SARS-CoV-2 PCR laboratory results • Primary care, national outpatient prescribing data • Permission to follow-up via record linkage for up to 10 years
Adding a second randomisation Key eligibility criteria 2. Need for ventilation; admission duration No additional treatment SECOND RANDOMISATION ELIGIBILITY CRITERIA Hypoxia (O 2 sat n <92% or on O 2 therapy) + Inflammation (CRP ≥75 mg/L) Lopinavir-ritonavir 1. Mortality at 28 days 400/100 mg bd PO for 10 days OUTCOMES Tocilizumab R Dexamethasone vs 6 mg od PO/IV for 10 days Control Hydroxychloroquine See protocol for dosing Azithromycin 500 mg od PO/IV for 10 days
Progress: Set-up Taking the front-foot 10 th March First draft protocol UK New Cases 13 th March Joint regulatory & ethics (IRB) submission 16 th March Regulatory approval. Chief Medical Officer letter to all hospitals. 17 th March IRB committee meeting 18 th March IRB approval received in writing 19 th March First Patient Enrolled (1 st protocol +9 days) 3rd April 1000 patients enrolled (FPE + 15 days)
Recruitment • >7,300 randomised at >160 hospitals • Typically 300 per day
Recommend
More recommend
